Colorectal cancer (CRC) is the second leading cause of cancer death in the United States. Most deaths are preventable through early detection, but failures of screening completion and quality substantially impair test effectiveness. This proposal unites the productive PROSPR I CRC Centers into a single collaboration to address key questions and pilot interventions to improve CRC screening outcomes. In PROSPR I, we developed a strong transdisciplinary, multisite collaboration. We collected 316 data elements, performed validation studies, created high-quality pooled data sets to identify patient, provider, and system gaps in the CRC screening process factors and published >60 manuscripts. Our unified PROSPR II Research Center (PRC) will use these proven collaborations and >10 years of longitudinal data for >8.9 million screen-eligible people (~ 1 of 40 eligible people in the US), large numbers of screening exposures (>8.4 million fecal immunochemical tests [FIT] and >1.9 million colonoscopies), and outcomes (>28,000 CRCs). Our PRC is geographically, demographically and economically diverse (three states, >800,000 African Americans, 1.6 million Hispanics, and 1 million Asian Americans). The health systems have different CRC screening patterns, different modalities, and include all major insurance/reimbursement methods (safety net, Medicare, Medicaid, high-deductible and pre-paid/fee-for-service, staff-model and incentivized providers). Our PROSPR I research identified major deficiencies in three areas of CRC screening: who should get screening and surveillance and when; why people do not complete recommended screening, surveillance or follow-up of positive tests; and how test quality and accuracy can be improved. Project 1 will identify on whom and when screening should be performed, particularly for those with conflicting recommendations (e.g., African Americans aged 40-49 years, and patients 76-85 years old). Project 2 will evaluate when surveillance should occur after a precancerous polyp diagnosis, using baseline colonoscopy results and precise new 10-year risk estimates for CRC. Project 3 will explore long-term screening patterns and multilevel drivers of why screening and surveillance are not appropriately completed, especially in understudied patients who never screen, fail to re-screen, use surveillance inappropriately or fail to follow up after a positive screening test. Project 4 will evaluate how to increase the effectiveness of FIT and colonoscopy by optimizing age- and sex-stratified quantitative FIT abnormal ranges, establishing precise adenoma detection thresholds for quality improvement and evaluating drivers of adenoma detection. We will use results from these observational studies, behavioral science methods, and stakeholder involvement to develop and pilot test multilevel interventions. Our transdisciplinary team of scientists, physicians, and healthcare experts will also provide leadership and data for trans-PROSPR, multiple-organ collaborations. The proposed research can substantially decrease the burden of CRC by reducing disparities and identifying ways to improve screening completion and effectiveness.